Diabetes and hypertension are two major risk factors for chronic kidney disease. Inappropriate activation of the intrarenal renin-angiotensin system (the hormone system that regulates blood pressure and water balance, RAS) substantially increases risk and progression to renal injury. Current treatments targeting the RAS only slow, rather than halt the progression to chronic kidney disease. Therefore, we urgently need to understand the mechanisms which activate this system and lead to increased blood pressure and renal injury in order to develop new therapeutic targets to control the progression to end-stage organ damage. Our long- term goal is to define the contributions of the newly discovered prorenin receptor in the collecting duct to the pathogenesis of hypertension and renal injury and to introduce a paradigm-challenging concept which explains the interaction between the prorenin receptor and prorenin in the collecting duct which highlights the functional roles of this interaction in the regulation of sodium reabsorption, blood pressure, and development and progression of renal fibrosis in diabetes mellitus and hypertension. Our central hypothesis is that during hypertension and hyperglycemia, the interaction between the prorenin receptor and prorenin in the collecting duct contribute to increased blood pressure and to the development and progression to renal injury by mechanisms that are both dependent and independent of angiotensin II, the major effector hormone of the renin-angiotensin system. This hypothesis will be tested addressing the following specific aims: (1) Demonstrate that the prorenin receptor is required for the activation of prorenin produced in the collecting ducts; (2) Determine the functional consequences of the interaction between prorenin and soluble prorenin receptor in the collecting duct during angiotensin II-dependent hypertension; and (3) Demonstrate that prorenin-dependent activation of membrane bound prorenin receptor to collecting duct cells leads to renal fibrosis during Streptozotocin-induced hyperglycemia. We will attain these specific aims using a vertical and innovated approach which will include in vivo and in vitro experiments using a unique mouse model developed by our laboratory with a specific genetic deletion of the prorenin receptor in the collecting duct. Experiments will be assessed using integrated physiological, molecular and histological methodologies. The successful completion of the research proposed is of great significance because findings will provide definitive in vivo evidence of the functional role of the prorenin receptor in the collecting duct, which will providea rationale for the generation of novel drugs targeting this receptor. Understanding the mechanism of this novel pathway will be of relevance to public health because it will allow the optimization of treatment in conditions associated with augmented prorenin receptor-prorenin interaction such as hypertension, diabetes, and preeclampsia.